Abstract

The present investigation was aimed to fabricate lyophilized nanosuspension of poorly soluble ethinylestradiol in order to enhance oral bioavailability and stability. The top-down high-pressure homogenization technique was used to formulate the desired dosage form. The formulations were characterized and optimized for compatibility, crystallographic investigation, surface topography, drug release, in vitro apoptosis and cytotoxicity and in vivo pharmacokinetic investigations. The mean particle size and zeta potential of the optimized lyophilized ethinylestradiol nanosuspension were 220±0.37 nm and -19.3±6.73 mV, respectively. The surface topographical studies showed needle-shaped particles from bar shape upon nanonization by high-pressure homogenization technique. Differential scanning calorimetry and X-ray powder diffraction studies confirmed the crystalline nature of ethynylestradiol after nanonization. The dissolution rate of ethinylestradiol nanosuspension was improved as compared to ethinylestradiol powder. In vitro cytotoxicity of ethinylestradiol nanosuspension on MCF-7 cell line showed more than 80 % inhibition of viability of cells relative to that produced by ethinylestradiol aqueous dispersion. Noteworthy, apoptotic cells treated with ethinylestradiol nanosuspension showed shrinkage, followed by fragmentation and cell death. Significantly, ethinylestradiol nanosuspension enhanced Cmax and AUC0-t by 1.5-fold and 1.7-fold compared to that of the aqueous solution. The relative bioavailability of ethinylestradiol was enhanced 2-fold and high concentrations were found to be distributed to liver, spleen and stomach. Thus lyophilized nanosuspension could be a better approach to enhance solubility, oral bioavailability and stability of ethinylestradiol in pharmaceutical formulations.